From 1916 to 1921, Sofronitsky studied in the Petrograd Conservatory under Leonid Nikolayev,[3] where Dmitri Shostakovich, Maria Yudina, and Elena Scriabina, the eldest daughter of the deceased Alexander Scriabin, were among his classmates. He met Scriabina in 1917 and married her in 1920.[4] While he had already divulged a sympathy for the piano music of the recently deceased mystic composer—as attested by Yudina—he now had a greater intellectual and emotional connection to Scriabin's works through his wife and through the Scriabin in-laws. Sofronitsky was also acclaimed as an outstanding pianist by the composer Alexander Glazunov and the musicologist and critic Alexander Ossovsky.

He gave his first solo concert in 1919,[4] and his only foreign tour in France between 1928 and 1929.[5] The only other time he performed outside the Soviet Union was at the Potsdam Conference in 1945, when he was suddenly sent by Stalin to play for the allied leaders.[6]

Sofronitsky taught at the Leningrad Conservatory from 1936 to 1942, and then at the Moscow Conservatory until his death.[7]

He gave many performances at the Scriabin Museum in Moscow, especially during the latter part of his career.[8]

Having met Scriabin's daughter only after her father's death, Sofronitsky never met the composer. Nevertheless, his wife vouched that the pianist was the most authentic interpreter of her late father's works. The other composer with whom Sofronitsky had the greatest affinity is Frédéric Chopin. He once told an interviewer: "A love for Chopin has followed me through the course of my entire life." Beyond Chopin and Scriabin, Sofronitsky had a wide repertoire spanning major composers from Johann Sebastian Bach to Nikolai Medtner and reaching as far as the works of Boris Goltz (1913–1942), with a focus on 19th-century Romantic composers and early 20th-century Russians.

Although little known in the West, never having toured or recorded there, Sofronitsky was held in the highest regard in his native land. Sviatoslav Richter and Emil Gilels looked up to Sofronitsky as their master, and famously, when Sofronitsky once drunkenly proclaimed that Richter was a genius, in return Richter toasted him and proclaimed him a god. Upon hearing of Sofronitsky's death, Gilels was reputed to have said that "the greatest pianist in the world has died."

Sofronitsky's recordings have not been issued systematically in the West. One noteworthy release, in BMG's "Russian Piano School" series, contains a complete concert, including a mercurial and highly praised account of Schumann's Piano Sonata No. 1, Op. 11. His issue in Philips' Great Pianists of the Twentieth Century features Chopinmazurkas and waltzes on the first CD and some of his legendary Scriabin on the second, including the 2nd (first movement), 3rd, 4th, and 9th sonatas and a performance of Vers la flamme. Denon Classics' (Japan) Vladimir Sofronitsky Edition is a series of 15 CDs, ten of which remain in print. Other Sofronitsky recordings have been issued by such labels as Arkadia, Arlecchino, Chant du Monde, Multisonic, Urania, and, most notably, Vista Vera, which has released seventeen volumes of Sofronitsky recordings as of April, 2010.